1. Field of the Invention
The present invention relates generally to the field of cancer and hyperproliferative cell therapy. More particularly, it concerns a methods for inhibiting the growth and/or killing of cells by contacting cells with a cytotoxic/cytostatic agent.
2. Description of Related Art
Normal tissue homeostasis is achieved by an intricate balance between the rate of cell proliferation and cell death. Disruption of this balance either by increasing the rate of cell proliferation or decreasing the rate of cell death can result in the abnormal growth of cells and is thought to be a major event in the development of cancer, as well as other cell proliferative disorders such as restenosis.
The effects of cancer are catastrophic, causing over half a million deaths per year in the United States alone. Conventional strategies for the treatment of cancer include chemotherapy, radiotherapy, surgery or combinations thereof, however further advances in these strategies are limited by lack of specificity and excessive toxicity to normal tissues. In addition, certain cancers are refractory to treatments such as chemotherapy, and some of these strategies such as surgery are not always viable alternatives. For example, non-small-cell lung cancer (NSCLC), which includes squamous cell carcinoma, adenocarcinoma and large-cell carcinoma, accounts for 75-80% of all lung cancers (American Cancer Society, 1993). Current multimodality therapeutic strategies applied to regionally advanced NSCLC are minimally effective with the overall cure rate being only about 10% (Belani, 1993; Roth et al., 1994).
Cancer is now understood to be the result of multiple genetic changes (Goyette et al., 1992; Klein et al., 1987) and it is well established that many cancers are caused, at least in part, by genetic alterations that result in either the over expression of one or more genes, or the expression of abnormal or mutant gene or genes. For example, the expression of oncogenes is known to play a role in the development of cancer. Oncogenes are defined as genetically altered genes whose mutated expression product somehow disrupts normal cellular function or control (Spandidos et al., 1989). These types of mutations are believed to have effects on the malignant growth of cells derived from practically every tissue.
Another type of gene of interest in the development of cancer is the tumor suppressor gene. Mutations in these genes result in loss of function of the normal cellular gene product, which are involved in the suppression of the neoplastic phenotype. The p53 gene is well recognized as a tumor suppressor gene (Montenarh, 1992). There is considerable evidence linking mutations in p53 in the oncogenesis of many human cancers. There are many reports demonstrating that the neoplastic growth of colon, glioblastoma, breast, osteosarcoma, and lung tumor cells can be suppressed by the expression of wild-type p53. For example, the introduction of wild-type p53 into a variety of cell types or tumors with p53 mutations or deletions, using viral delivery methods, has resulted in the expression of the wild-type p53 transgene and a suppression of the malignant phenotype. Furthermore, introduction of wild type 53 into certain types of p53 wild type tumor cells suppresses their growth. These types of observations demonstrate that high levels of expression of wild-type p53 are a desirable effect for the treatment of p53-dependent oncogenic malignancies.
Other types of hyper-proliferative disorders have also been the target of gene therapy. Restenosis, characterized by the regrowth of smooth muscle cells into the lumen of blood vessels following angioplasty or other arterial damage, is a frequent and recurring problem in the long term success of angioplasty. The failure rates of angioplasty as a result of restenosis within six months are reported to be between 25-50% (Leimgruber et al., 1986; Gruentzieg et al., 1987; Nobuyoshi et al., 1988; Serruys et al., 1988). Restenosis also occurs after arterial reconstructions, atherectomy, stent implantation, and laser angioplasty. Injury to arteries during angioplasty results in the activation of medial smooth muscle cells, which begin to migrate and proliferate into the lumen of the artery to form a neointima, or a new layer of cells. It is believed that expansion of this neointima as a result of the new layer of smooth muscle cells, extracellular matrix, and recruited inflammatory cells, is the cause of the eventual reduction of blood flow through the artery and recurrence of ischemic symptoms. Currently it is believed that the administration of gene therapy constructs encoding the HSV-thymidine kinase or cytosine deaminase gene may be beneficial to prevent restenosis. Similarly, it is envisioned that gene therapy may be useful for the treatment of other hyper-proliferative cellular disorders including psoriasis and rheumatoid arthritis.
Generally, both standard chemo- and radiotherapies, as well as transfer of genetic material into cells, have limitations; there clearly remains a need for improved strategies of anti-cancer and anti-proliferative cell therapy. In particular there is a need to increase the level of growth inhibition beyond that induced by traditional gene therapy modalities.